7-aminothiazolo-(5,4-d) pyrimidine



pyrimidines (purines).

United States, Patent No Drawing. Application December 28, 1954 Serial No. 478,200 1 Claim. (Cl. 260-2565) The present invention relates to thiazolo(5,4-d) pyrimidines and the method of preparing the same.

In a further aspect, the invention contemplates a novel method of preparing valuable intermediates which are useful in the preparation of G-mercaptopurine and closely related derivatives having valuable properties in the treatment and alleviation of the symptoms which accompany human leukemias.

Thiazolo (5,4-d) pyrimidines are of interest because of the structural analogy to the imidazolo (5,4-d) Earlier attempts to prepare the analogues of the natural purines gave examples with additional substituents (e.g. 2-phenyl, 2-methyl, sec Falco and Hitchings, J. Am. Chem. Soc., 72, 3203 (1950)) but the methods then employed failed to provide the substances with hydrogen in the 2-position.

In the parent application Serial No. 425,036, now Patent No. 2,721,866, filed April 22, 1954, a method of synthesis of a 6-mercaptopurine from 4,5-diamino-6-mercaptopyrimidine is described. In the reaction of the latter with formic acid there was formed under specified conditions, not the expected 4-amino-5-formamido-6-mercaptopyrimidine but 7-aminothiazolo (5,4-d) pyrimidine. On treatment with alkali the sodium salt of the formamido compound is formed and may be converted to 6-mercaptopurine as described in Serial No. 425,036, now Patent No. 2,721,866. The 7-aminothiazolo (5,4-d) pyrimidine is thus useful as an intermediate in the preparation of fi-mercaptopurine.

The compounds which are the subject of the present invention are represented by the formula drogcn. It has been found according to the invention that these compounds may be readily prepared by reaction involving the treatment of a 4,5-diamino-6-mercaptm pyrimidine with concentrated formic acid. The resulting thiazolo derivative is then easily converted to 6-mercaptopyrimidine or related compounds by treatment with alkali and subsequent neutralization of the alkali salt of 6- mercaptopurine. The method of the invention may be illustrated as follows:

sset kw NH:

SCH SH II N N L l t l NH N N 7-aminotl1iazolo (5,4-d) pyrimidine 5 2,933,498 Patented Apr. 19, 1960 EXAMPLE I 4,5-diamino 6-mercapt0pyrimidine 7.5- grams; of 4-amino-6-chloro-5-nitropyrimidine was suspendedin 20.0 ml. of 1 N-potassium hydrosulphide and heated on the steam bath for two hours while passing. hydrogen sulphidethrough the reaction mixture. The reaction mixture was allowed to cool slowly, acidified with 10 N sulphuric acid and chilled. The precipitate consisted: of 4,5f-diamino-6-mercaptopyrimidine and sulphur. It. wasboiled with-.300.ml. of water, filtered hot andthen chilled. The product precipitated as pale yellow needles (4.2 g.); an additional 0.95 g. was obtained by concentration of the mother liquors to ml. The ultraviolet absorption spectrum of 4.5-diamino-6-mercaptopyrimidine shows maxima at 240 and 305 III/J. at pH 1 and at 240 and 310 mp. at pH 11.

7-amin0-thiazolo (5 ,4-d -pyrimidine A mixture of 2 g. of 4,5-diamino-6-mercaptopyrimidine and 10 ml. of 98% formic acid was heated at 70 for two hours and then evaporated to dryness on the steam bath. The residue, 7-amino-thiazolo (5,4-d) pyrimidine has an ultraviolet absorption spectrum completely different from the starting material Amax.=263 mp at pH 1; Amax.=261 my. at pH 11.

6-mercapt0purine 7-aminothiazol0 (5,4-d) pyrimidine 9 g. of 4,5-diamino-6-mercaptopyrimidine was allowed to stand with 100 ml. of 98% formic acid for 2 days at room temperature. The mixture was evaporated to dryness on the steam bath and the residue recrystallized from 200 ml. of water, adjusted to pH 7 with ammonium hydroxide. On cooling, colorless needles of 7-aminothiazolo (5,4-d) pyrimidine precipitated, M.P. 214 (yield=7.1 g.). The ultraviolet absorption spectrum shows a single band with )tmax.=263 mu at pH 1 and pH 11.

EXAMPLE III 5,7-diamin0thiazolo (5,4-d) pyrimidine 0.5 g. of 2,4,S-triamino-6-mercaptopyrimidine was heated with 30 ml. of 98% formic acid at 100 for five hours and the solution was then evaporated to dryness on the steam bath. The residue was suspended in 50 ml. of water and the pH adjusted to 8 with ammonium hydroxide. The insoluble material was removed by filtration. The5,7-diaminothiazolo (5,4-d) pyrimidine which was obtained by evaporation of the aqueous filtrate to dryness, and extraction of the residue with 50 ml. of ethyl alcohol. Evaporation of the alcoholic solution gave 5,7-diaminothiazolo (5,4-d) pyrimidine which shows the following ultraviolet absorption spectrum: kmax.=265 my. at pH 1 and Amax.=285 my. at pH 11.

3 r XAMPLE 1v 5,7-dihydrbxythiazolo (5,4-d) pyrimidine A suspension of 100 mg. of 2,4-dihydroxy-5-amino-6- mercaptopyrimidine in ml. of98 100%" formic acid was heated on the "steam bath for four hours; The mixture was then evaporated to dryness, and the residue dissolved in ml. of 0.2 N sodium hydroxide. The alkaline solution was filteredaud acidified to pH 5 with glacial acetic acid. The crystalline precipitate ofi5,7-dihydroxythiazolo (5,4-d) pyrimidine has-an ultraviolet absorption spectrum with Amax.=248 my at pHl and Amax. =28$f at pH 11. V

'- EXAMPLE Y 7-hydroxythiqzolo (5,4-d) pyridine 3 g. of 7-aminothiazolo (5,4-d) pyrimidine was dissolved in 40 ml. of 1 N hydrochloric acid; The solution was heated to and a solution of 1.5 g. of sodium nitrite in 10 mlpof water was added dropwise in the course of 10 minutes, as the temperature was gradually raised to The mixture was kept at 90-95 for an- .other 5 minutes, cooled and the acidity was adjusted to pH 4 by additon of 10 ml. of 2 N sodium hydroxide. The precipitate of 7-hydroxythiazolo (5,4-d) pyrimidine.(1. 9 g.) was filtered 701T and recrystallized from 20ml. of hot water. The product has an ultraviolet absorptiou spectrum with a kmax. at 258 mp at pH 1 and pH 11.

We claim:

7-aminothiazolo (5,4-d)'-pyrimidine.

No references cited. 

